Costimulatory B7 molecules (B7-1 or CD80; and B7-2 or CD86) are known to bind to T cell costimulatory receptors CD28 and CTLA4. Engagement of CD28 is know to transduce signals in T cells that play a critical role in T cell activation; however, little is known of the ability of B7 molecules to themselves act as signal transducing molecules. The effect of B7-1 and B7-2 crosslinking was assessed in the B cell lymphoma BAL.17. Initial studies demonstrated that B7 crosslinking induces AP-1 components including c-fos and c-jun, as demonstrated by gel retardation and "super-shift" assays. These findings indicate that B7 engagement by counter-receptors such as CD28 or CTLA4 may lead to bidirectional effects, functioning to transduce signals in B7-expressing cells such as B lymphocytes, in addition to signaling CD28/CTLA4 positive T cells. The role of CD28/B7 interactions has been analyzed in host responses to antigenic tumor. EL4 tumor cells grew progressively in syngeneic B6 mice. However, transfection of EL4 with B7-1 or B7-2 costimulatory ligands resulted in tumor rejection and the induction of tumor-specific immunity. Tumor rejection under these conditions was dependent upon the presence of the B7 receptor CD28 as demonstrated using CD28-deficient B6 mice for tumor challenge. These results demonstrated for the first time the requirement for CD28 as a B7 receptor in tumor rejection. The role of B7 cytoplasmic domains in tumor rejection was tested by transfection of EL4 cells with cytoplasmic deletion mutants of B7-1 and B7-2, and it was found that tumor rejection was not influenced by the presence or absence of B7 cytoplasmic domains. These results indicate that CD28 interaction with extracellular B7-1 or B7-2 domains can mediate costimulatory function for syngeneic tumor rejection. The effect of costimulus in T cell development and repertoire selection was studied using transgenic mice that over-express B7-1(CD80) or B7-2 (CD86). Initial data indicate that expression of costimulatory B7 ligands has a substantial effect on CD4 and CD8 differentiation. Further studies are in progress to assess the mechanism of this effect. TCR mediated activation of T cells to proliferation and IL2 secretion is enhanced in mice deficient in cbl-b, suggesting a negative regulatory role for cbl-b under these conditions. Studies are in progress using cbl-b deficient mice to assess the role of cbl-b in susceptibility to apoptosis and to anergy induction, as well the effect on T cell repertoire selection.